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CAMP Metabolism Controls Caspase-11 Inflammasome Activation and Pyroptosis in Sepsis

Overview
Journal Sci Adv
Specialties Biology
Science
Date 2019 May 28
PMID 31131320
Citations 79
Authors
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Abstract

The ability of cytosolic lipopolysaccharide (LPS) to activate caspase-11-dependent nonclassical inflammasome is intricately controlled to avoid excessive inflammatory responses. However, very little is known about the regulatory role of various metabolic pathways in the control of caspase-11 activation. Here, we demonstrate that l-adrenaline can act on receptor ADRA2B to inhibit the activation of the caspase-11 inflammasome by cytosolic LPS or infection in macrophages. l-adrenaline-induced cAMP production via the enzyme ADCY4 promotes protein kinase A (PKA) activation, which then blocks the caspase-11-mediated proteolytic maturation of interleukin-1β, gasdermin D (GSDMD) cleavage, and consequent DAMP release. Inhibition of PDE8A-mediated cAMP hydrolysis limits caspase-11 inflammasome activation and pyroptosis in macrophages. Consequently, pharmacological modulation of the ADRA2B-ADCY4-PDE8A-PKA axis, knockout of ( ), or inactivation ( ) similarly protects against LPS-induced lethality in poly(I:C)-primed mice. Our results provide previously unidentified mechanistic insight into immune regulation by cAMP and represent a proof of concept that immunometabolism constitutes a potential therapeutic target in sepsis.

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References
1.
Beutler B, Rietschel E . Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol. 2003; 3(2):169-76. DOI: 10.1038/nri1004. View

2.
Cheng K, Xiong S, Ye Z, Hong Z, Di A, Tsang K . Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J Clin Invest. 2017; 127(11):4124-4135. PMC: 5663346. DOI: 10.1172/JCI94495. View

3.
Catherine Jin S, Conti M . Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses. Proc Natl Acad Sci U S A. 2002; 99(11):7628-33. PMC: 124305. DOI: 10.1073/pnas.122041599. View

4.
Yang L, Xie M, Yang M, Yu Y, Zhu S, Hou W . PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat Commun. 2014; 5:4436. PMC: 4104986. DOI: 10.1038/ncomms5436. View

5.
Aronoff D, Canetti C, Serezani C, Luo M, Peters-Golden M . Cutting edge: macrophage inhibition by cyclic AMP (cAMP): differential roles of protein kinase A and exchange protein directly activated by cAMP-1. J Immunol. 2005; 174(2):595-9. DOI: 10.4049/jimmunol.174.2.595. View